Angiogenesis literally means the birth of new blood vessels. (In Greek, “angio” means blood vessel and “genesis” means birth or beginning). Under controlled physiologic conditions it is a normal and essential process. For example, angiogenesis is a necessary part of fetal development, wound healing, and recovery from a heart attack. However, during the process of cancer growth and spread, angiogenesis allows the tumor to make its own blood supply in order to obtain the nutrients and oxygen it needs for survival. The result is a web of vessels that allows the tumor to grow even more and spread (metastasize) to other far away organs.
As the tumor grows and recruits more and more blood supply, a network of small capillaries forms and becomes disorganized. There is lack of direction to the flow of blood and empty vessels form frequently. Thus the chaotic vascular system formed results in increased pressure. As the pressure increases these vessels become “leaky”. “Leaky” vessels cause the build up of proteins and plasma in the tumor mass itself forming edema. As the edema builds, tumor cells will become more starved for oxygen and other nutrients. Lack of oxygen, in turn, causes the cancer cells to secrete even more VEGF and propagate this vicious cycle.
Most angiogenesis inhibitors (anti-angiogenic drugs) work by either binding to the signaling protein (VEGF) and thereby not allowing it to interact with its complementary receptor on the endothelial cell, or, by binding to the receptor and blocking any interactions with its respective protein.
Atherosclerosis is a common form of arteriosclerosis that results from the development of an intimal lesion and subsequent narrowing of the vessel lumen. As the lesions increase in size, they reduce the diameter of the arteries and impede blood circulation. The formation of the atherosclerotic lesion is typically classified in five overlapping stages—(1) migration of smooth muscle cells, (2) lipid accumulation, (3) recruitment of inflammatory cells, (4) proliferation of vascular smooth muscle cells, and (5) extracellular matrix deposition. In a healthy vessel, the vast majority of the smooth muscle cells are contained in the vessel media. As lesions develop, smooth muscle cells migrate from the media to the intima of the vessel. Although smooth muscle cells in healthy vessel walls do not significantly accumulate lipid, the intimal smooth muscle cells have an increased capacity for lipid uptake and storage.
Lipid-conjugates having a pharmacological activity of inhibiting the enzyme phospholipase A2 (PLA2, EC 3.1.1.4) are known in the prior art. Phospholipase A2 catalyzes the breakdown of phospholipids at the sn-2 position to produce a fatty acid and a lysophospholipid. The activity of this enzyme has been correlated with various cell functions, particularly with the production of lipid mediators such as eicosanoid production (prostaglandins, thromboxanes and leukotrienes), platelet activating factor and lysophospholipids. Since their inception, lipid-conjugates have been subjected to intensive laboratory investigation in order to obtain a wider scope of protection of cells and organisms from injurious agents and pathogenic processes.